Recent advances in neuroscience are making clear the natural shape of neurotransmitter', substances deeply related to memory in the brain. It is said that some of these substances are neuropeptides containing prolines.
Recovery of the memory was reported by the dosing neuropeptide containing proline to experimental amnesia rats (See Science 211, 601 (1981)).
On the other hand, it is presumed that these neuropeptide-hormones shall be metabolized by cerebral endogenous peptidases. Especially, prolyl endopeptidase (EC, 3. 4. 21. 26) might take part in these metabolisms closely (See J. Biochem., 94, 1179 (1983)).
From these facts, the studies were in progress that it should be possible to prevent or treat amnesia by inhibiting prolyl endopeptidase and suppressing the metabolism of neutrotransmitters. (See Protein, Nucleic acid and Enzyme 25(6), 513(1980); Nippon Nougei Kagaku Kaishi 58(11), 1147(1984); J. Neurochem., 41, 69(1983); ibid 42, 237(1984).)
For the purpose described above, several compounds were synthesized. For example, it is clear that N-benzyloxycarbonyl-glycyl-L-prolyl-chloromethane, N-benzyloxycarbonyl-L-prolyl-prolinal strongly inhibit prolyl endopeptidase (See J. Neurochem., 41, 69 (1983)). More recently, it is disclosed the compounds shown below are effective for the above purpose.
With the proviso that, R.sup.3, R.sup.4, R.sup.5 independently represent hydrogen atom, halogen atom, hydroxy group, lower alkyl group, phenyl group which is unsubstituted or substituted, EQU --CH.sub.2 R.sup.9, --X--R.sup.10, --O--CO--R.sup.12, --NH.sub.2, --NHR.sup.14
or NR.sup.17 R.sup.18, {with proviso that R.sup.9 represents phenyl group which is unsubstituted or substituted. X represents an oxygen atom or sulfur atom. R.sup.10 represents lower alkyl group, phenyl group which is substituted or unsubstituted or --CH.sub.2 R.sup.11, (with the proviso that R.sup.11 represents phenyl group which is unsubstituted or substituted. R.sup.12 represents lower alkyl group, phenyl group which is unsubstituted or substituted or --CH.sub.2 R.sup.13, (with proviso that R.sup.13 represents phenyl group which is unsubstituted or substituted. R.sup.15 represents lower alkyl group, cycloalkyl group of 5 or 6 ring members, phenyl group which is unsubstituted or substituted, --CH.sub.2 R.sup.15, (with the proviso that R.sup.15 represents phenyl group unsubstituted or substituted or --CO--R.sup.16 (with the proviso that R.sup.16 represents lower alkyl group or phenyl group which is unsubstituted or substituted. R.sup.17 and R.sup.18 independently represent lower alkyl group or --CH.sub.2 R.sup.19, with the proviso that R.sup.19 represents phenyl group which is unsubstituted or substituted.}
R.sup.6 represents a hydrogen atom or lower alkyl group. R.sup.7 represents a hydrogen atom, lower alkyl group, benzyl group, CH.sub.3 --CH(OH)--or--(CH.sub.2).sub.n --
R.sup.20 , with the proviso that n represents an integer of from 0 to 4. R.sup.20 represents ##STR6## with the proviso that R.sup.21 represents hydrogen atom, lower alkyl group or benzyl group, or heterocyclic ring group. R.sup.8 represents hydrogen atom or 5-membered heterocyclic ring group together with R.sup.7 and nitrogen atom and carbon atom which are neighboured. R.sup.22 represents phenyl group which is unsubstituted or substituted. See Japanese Patent Kokai No. 62-221666, i.e., European Patent Publication No. 238319.
The present inventors have also filed an application related to prolinal derivatives having an activity of anti-amnesia, in advance of the present application, i.e.;